Biology Reference
In-Depth Information
Introduction to Virus Entry
The ability of a virus to enter a host cell and deliver its genome for replication
represents the essential, first step in the replication cycle of the virus. Human
cytomegalovirus (HCMV), like most herpesviruses, enters cells via direct fusion
of the viral envelope with the plasma membrane at neutral pH (Compton et al.
1992). However, in specific cell lines such as retinal pigment epithelial and
endothelial cells, HCMV enters by receptor-mediated endocytosis, requiring
low-pH (Bodaghi et al. 1999; Ryckman et al. 2006). Regardless, the HCMV
entry process is highly complex, requiring multiple envelope glycoproteins,
which interact with a series of cellular receptors.
The HCMV genome is predicted to encode over 50 glycoproteins and the virion
itself has been determined by mass spectrometry to consist of at least 19 different
envelope proteins (Varnum et al. 2004; reviewed in Mocarski et al. 2007). However,
of these, only five glycoproteins are essential for virus replication in vitro (reviewed
in Mocarski et al. 2007). These include glycoprotein B (gB; UL55), gM/gN
(UL100/UL73), and gH/gL (UL75/UL115) (reviewed in Mocarski et al. 2007).
Glycoprotein M, the most abundant glycoprotein, accounting for 10% of the virion
mass, is complex with gN and acts as an attachment receptor (Kari and Gehrz 1992;
Compton et al. 1993; Mach et al. 2000; Varnum et al. 2004). Glycoprotein B, the
second most abundant glycoprotein, is both an attachment and fusion receptor (Kari
and Gehrz 1992; Compton et al. 1993; Navarro et al. 1993; Bold et al. 1996;
Varnum et al. 2004). Glycoprotein H is a fusion receptor, while gL is a chaperone
required for gH localization; both are complexed with gO (UL74), a glycoprotein
unique to HCMV, which enhances virus entry (Keay and Baldwin 1991; Huber and
Compton 1997, 1998).
Alternatively, the gH/gL complex associates with pUL128 and pUL130, con-
ferring epithelial and endothelial cell tropism to clinical isolates of HCMV
(Wang and Shenk 2005). The UL131-128 locus is consistently mutated in labora-
tory-adapted strains such as AD169 and Towne, which do not replicate well in
endothelial or epithelial cells (reviewed in Mocarski et al. 2007). An AD169
strain in which the UL131 locus has been repaired (BAD r UL131) forms both
gH/gL/gO and gH/gL/pUL128/pUL130 complexes and is also restored for its
ability to infect epithelial and endothelial cells (Wang and Shenk 2005).
Cellular Receptors Proposed for HCMV Entry
One characteristic of HCMV entry is its broad cellular tropism, leading to
the manifestation of disease in almost every tissue type and organ system in
the human host. In vitro, HCMV is able to enter a wide variety of cell types,
including dendritic, endothelial, epithelial, fibroblast, and monocyte/macro-
phage cells (Mocarski et al. 2007). The ability of HCMV to enter such a wide
variety of cell types indicates the presence of a large number of cellular
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